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      FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/ β-catenin signalling

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          Abstract

          Background:

          FAT4, a cadherin-related protein, was shown to function as a tumour suppressor; however, its role in human gastric cancer remains largely unknown. Here, we investigated the role of FAT4 in gastric cancer and examined the underlying molecular mechanisms.

          Methods:

          The expression of FAT4 was evaluated by immunohistochemistry, western blotting, and qRT–PCR in relation to the clinicopathological characteristics of gastric cancer patients. The effects of FAT4 silencing on cell proliferation, migration, and invasion were assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, and migration and invasion assays in gastric cancer cell lines in vitro and in a mouse xenograft model in vivo.

          Results:

          Downregulation of FAT4 expression in gastric cancer tissues compared with adjacent normal tissues was correlated with lymph-node metastasis and poor survival. Knockdown of FAT4 promoted the growth and invasion of gastric cancer cells via the activation of Wnt/ β-catenin signalling, and induced epithelial-to-mesenchymal transition (EMT) in gastric cancer cells, as demonstrated by the upregulation and downregulation of mesenchymal and epithelial markers. Silencing of FAT4 promoted tumour growth and metastasis in a gastric cancer xenograft model in vivo.

          Conclusions:

          FAT4 has a tumour suppressor role mediated by the modulation of Wnt/ β-catenin signalling, providing potential novel targets for the treatment of gastric cancer.

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          The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network.

          Kieran F. Harvey, Nicolas Tapon (2007)
          Intense research over the past four years has led to the discovery and characterization of a novel signalling network, known as the Salvador-Warts-Hippo (SWH) pathway, involved in tissue growth control in Drosophila melanogaster. At present, eleven proteins have been implicated as members of this pathway, and several downstream effector genes have been characterized. The importance of this pathway is emphasized by its evolutionary conservation, and by increasing evidence that its deregulation occurs in human tumours. Here, we review the main findings from Drosophila and the implications that these have for tumorigenesis in mammals.
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            A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling.

            K Miyatake, Akira Iimura, Eisuke NISHIDA … (2012)
            The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/β-catenin signalling through their interaction with β-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/β-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of β-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to β-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/β-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of β-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of β-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of β-catenin.
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              Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

              Luc Morris, Andrew M. Kaufman, Yongxing Gong … (2013)
              Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo, by normally binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis, and impacts patient survival. Together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings unify two outstanding questions in cancer biology: the basis of Wnt activation in non-colorectal tumors, and the identity of a 4q35 tumor suppressor.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 22 December 2015
                Publication date (Electronic): 03 December 2015
                Volume: 113
                Issue: 12
                Pages: 1720-1729
                Affiliations
                [1 ]Department of General Surgery, Institute of Anal-Colorectal Surgery , No. 150 Central Hospital of PLA, No. 2, Huaxiaxi Road, Luoyang 471031, China
                [2 ]Department of General Surgery, The No. 150 Clinical Medical College, Second Military Medical University , Shanghai 200433, China
                [3 ]Department of Oncology, Shanghai Changhai Hospital , 168 Changhai Road, Shanghai 200433, China
                [4 ]Department of Gastrointestinal Surgery, Shanghai Changzheng Hospital , 415 Fengyang Road, Shanghai 200003, China
                Author notes
                [5]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: bjc2015367
                DOI: 10.1038/bjc.2015.367
                PMC ID: 4701992
                PubMed ID: 26633557
                SO-VID: d4f3fa60-bfe4-493b-83b7-d7e6ddee65b2
                Copyright © Copyright © 2015 Cancer Research UK
                License:

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                Date received : 28 January 2015
                Date revision received : 14 August 2015
                Date accepted : 23 September 2015
                Categories
                Subject: Molecular Diagnostics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: fat4,gastric cancer,metastasis,wnt/β-catenin,emt
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: fat4, gastric cancer, metastasis, wnt/β-catenin, emt

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